Activation and expansion of dengue virus‐specific T cells and abnormal liver functions in dengue patients have been documented. However, it remains to be determined whether T cells are involved in the pathogenic mechanism of dengue virus infection. In this study, immunocompetent C57BL/6 mice were employed to study dengue virus‐induced T cell activation. Mice were inoculated with 10⁸ PFU dengue virus serotype 2 strain 16681 by the intravenous route. Dengue viral core RNA was detected by RT‐PCR in mouse serum, liver, spleen, and brain at different time points after infection. Splenic T cells were activated as evidenced by their expression of CD69 and O‐glycosylated CD43 at as early as day 3 after infection. Splenic T cell expression of O‐glycosylated CD43 and IFN‐γ production coordinately peaked at day 5. Coincided with the peak of splenic T cell activation was hepatic lymphocyte infiltration and elevation of liver enzymes. Flow cytometric analysis revealed the infiltrating CD8⁺ T cell to CD4⁺ T cell ratio was 5/3. After a second inoculation of dengue virus, hepatic T cell infiltration and liver enzyme levels increased sharply. The infiltrating hepatic CD8⁺ T cell to CD4⁺ T cell ratio increased to 5.8/1. A strong correlation was found between T cell activation and hepatic cellular infiltration in immunocompetent mice infected with dengue virus. The kinetics of liver enzyme elevation also correlated with that of T cell activation. These data suggest a relationship between T cell infiltration and elevation of liver enzymes. J. Med. Virol. 73:419–431, 2004. © 2004 Wiley‐Liss, Inc.